# Elucidation of Molecular Mechanisms of Lipid-Altered Cytotoxicity of TDP-43 Fibrils

## TL;DR

This study explores how lipids influence the aggregation and toxicity of TDP-43 protein, which is linked to several neurodegenerative diseases.

## Contribution

The study reveals that specific lipid bilayers alter TDP-43 fibril cytotoxicity and affect cellular processes like autophagy and endosome damage.

## Key findings

- Anionic phosphatidylserine and cardiolipin lipid bilayers accelerate TDP-43 aggregation.
- TDP-43 fibrils damage endosomes and impair autophagy in dopaminergic cells.
- Lipid-induced changes in TDP-43 fibrils trigger an unfolded protein response in the endoplasmic reticulum.

## Abstract

Progressive aggregation
of TAR DNA-binding protein 43 (TDP-43)
is a hallmark of numerous neurodegenerative diseases, including amyotrophic
lateral sclerosis, frontotemporal dementia, Alzheimer’s disease,
and limbic predominant age-related TDP-43 encephalopathy (LATE). This
highly conserved nuclear RNA/DNA-binding protein is involved in the
regulation of RNA processing. The C-terminal domain (CTD) of TDP-43
plays a key role in protein solubility, cellular localization, and
protein–protein interactions. CTD is rich in glycine, glutamine,
and asparagine, which facilitate TDP-43 aggregation into amyloid oligomers
and fibrils observed in the brain. In this study, we examine the role
of lipid bilayers in the aggregation properties of the CTD of TDP-43.
We found that lipid bilayers composed of anionic phosphatidylserine
and cardiolipin accelerated TDP-43 aggregation. Although lipids did
not alter the secondary structure, they altered the cytotoxicity that
TDP-43 fibrils exerted to rat dopaminergic cells. Using molecular
methods, we showed that TDP-43 fibrils damage cell endosomes. This
causes aggregate leakage into the cytosol, where TDP-43 fibrils impair
cell autophagy, simultaneously triggering a severe unfolded protein
response in the endoplasmic reticulum. Our results indicate that TDP-43
aggregation may be linked to pathological changes in the lipid profiles
of neurons.